Current Drug Metabolism - Volume 20, Issue 9, 2019

Background: Traditional Chinese medicine (TCM) has been used for medical purposes since the ancient time and has gradually gained recognition worldwide. Nowadays, patients with thrombus presiding to anticoagulant/ antiplatelet drugs prefer taking TCM. However, an increasing number of studies on herb–drug interactions have been shown. Nevertheless, findings are frequently conflicting and vague. In this review, we discuss the herb–drug interactions between TCM and anticoagulant/antiplatelet drugs to provide guidance on concomitant ingestion with anticoagulant/antiplatelet drugs. Methods: We undertook a structured search of medicine and drug databases for peer-reviewed literature using focused review questions. Results: Danshen, Ginkgo, Ginger, H. Perforatum, SMY and Puerarin injection had directional regulation effects on the efficacy of anticoagulant drugs by altering the CYPs, pharmacokinetic indexs and hemorheological parameters. H. Perforatum inhibited the efficacy of Clopidogrel by enhancing the CYP3A4 activity and Ginkgo increased the efficacy of Ticlopidine. Additionally, Renshen, the formulae except SMY and injections except Puerarin injection could increase or decrease the efficacy of anticoagulant/antiplatelet drugs via regulating the CYPs, platelet aggregation, hemorheological parameters and others. Conclusion: Some cases have reported that TCMs may increase the bleeding risk or has no effect on coagulation when anticoagulant/antiplatelet drugs are concurrently used. However, pharmacokinetic studies have presented either consistent or slightly varying results. So it is difficult to ascertain whether the concurrent use of TCM may increase or reduce the pharmacologic effects of anticoagulant/antiplatelet drugs with adverse reactions. Therefore, herb–drug interactions of TCM and anticoagulant/antiplatelet drugs should be further explored and defined.

Background: A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with its expanding use in clinical practice. The drug requires regular monitoring given its wide range of adverse effects including bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage, and neurotoxicity. The toxicity usually occurs rapidly and leads to severe neutropenia, sepsis, and advanced renal failure that are difficult to manage. Methods: This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory evaluation, and treatment of patients with methotrexate overdose. High-quality literature of the past six decades was collected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and the Cochrane Library, that have important implications in current clinical practice. Results: Methotrexate overdose has complex toxicokinetic and produces myriad clinical features mimicking conditions of lesser severity. Organ dysfunction related to bone marrow, kidney or central nervous system is lifethreatening. The management should focus on high-quality supportive care, antidotal therapy (folinic acid and carboxypeptidase- G2) and plasma alkalization. Conclusion: In accordance with the dictum “prevention is better than cure”, the author emphasizes on the role of patient education, regular clinical observation, and laboratory monitoring for prompt recognition and diagnosis of methotrexate overdosing at the earliest stage.

Background: The main drawbacks for using conventional antimicrobial agents are the development of multiple drug resistance due to the use of high concentrations of antibiotics for extended periods. This vicious cycle often generates complications of persistent infections, and intolerable antibiotic toxicity. The problem is that while all new discovered antimicrobials are effective and promising, they remain as only short-term solutions to the overall challenge of drug-resistant bacteria. Objective: Recently, nanoantibiotics (nAbts) have been of tremendous interest in overcoming the drug resistance developed by several pathogenic microorganisms against most of the commonly used antibiotics. Compared with free antibiotic at the same concentration, drug delivered via a nanoparticle carrier has a much more prominent inhibitory effect on bacterial growth, and drug toxicity, along with prolonged drug release. Additionally, multiple drugs or antimicrobials can be packaged within the same smart polymer which can be designed with stimuli-responsive linkers. These stimuli-responsive nAbts open up the possibility of creating multipurpose and targeted antimicrobials. Biofilm formation still remains the leading cause of conventional antibiotic treatment failure. In contrast to conventional antibiotics nAbts easily penetrate into the biofilm, and selectively target biofilm matrix constituents through the introduction of bacteria specific ligands. In this context, various nanoparticles can be stabilized and functionalized with conventional antibiotics. These composites have a largely enhanced bactericidal efficiency compared to the free antibiotic. Conclusion: Nanoparticle-based carriers deliver antibiotics with better biofilm penetration and lower toxicity, thus combating bacterial resistance. However, the successful adaptation of nanoformulations to clinical practice involves a detailed assessment of their safety profiles and potential immunotoxicity.

Background: Long-term intake of a high-fat diet is a crucial factor contributing to obesity, which has become a global public health problem. Progressive obesity subsequently leads to hepatic injury, renal damage and intestinal atrophy. Transporters expressed in the liver, kidney and intestine play important roles in the deposition of nutrients and drugs, but researchers have not clearly determined whether/how the expression of transporters changes after long-term administration of a High-Fat Diet (HFD). This study aims to explore the effects of the long-term administration of a HFD on the expression of drug transporters in the liver, kidney and intestine in mice and to provide useful information for medical applications in the clinic. Methods: Male C57BL/6J mice were fed either a basal diet or HFD for 24 weeks, and oral glucose tolerance tests were performed after 3, 11 and 23 weeks. Serum was obtained to measure lipid metabolism, inflammatory mediators, renal function and hepatic function. Adipose tissues, kidney, pancreas and liver were collected for hematoxylin and eosin (H) staining after 4, 12 and 24 weeks. The mRNA and proteins expression of drug transporters in the liver, kidney and intestine were detected using real-time PCR and western blot, respectively. Results: Compared with the control group, long-term HFD administration significantly increased the adipose index. The serum lipid levels, including Total Cholesterol (TC), Triglyceride (TG), and Low-Density Lipoprotein Cholesterol (LDL-C), as well as the levels of the inflammatory cytokines Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) were significantly elevated in HFD-induced obese mice. H staining revealed pathological changes in the adipose cells, liver, kidney and pancreas from the obese group following the long-term administration of the HFD. The liver of the obese group presented increased mRNA expression of the efflux transporter Mrp2 and uptake transporter Oat2 at 24 weeks. The relative expression of Oat2 increased 4.08-fold and the protein expression of Oat2 was upregulated at 24 weeks in HFD-fed mice, while the mRNA expression of the uptake transporters Oct1, Oatp1b2 and Oatp1a4 decreased by 79%, 61% and 19%, respectively. The protein expression of Oct1 was significantly downregulated in obese mice at 12 weeks. The mRNA expression of the efflux transporter Mdr1a was significantly reduced in HFD-fed mice compared with the control group at 24 weeks. Western blot showed that the trend of protein level of Mdr1 was consistent with the mRNA expression. In the kidney, the level of the Oct2 mRNA increased 1.92- and 2.46-fold at 4 and 12 weeks in HFD-fed mice, respectively. The expression of the Oat1 and Oat3 mRNAs was markedly downregulated in the kidneys of mice with HFD-induced obesity at 4 weeks. The decrease of 72% and 21% in Mdr1a mRNA expression was observed in the obese model at 4 weeks and 12 weeks, respectively. Western blot showed that the protein levels of Mdr1 and Oat1 were consistent with the mRNA expression. The qPCR experiments showed a 2.87-fold increase in Bcrp mRNA expression at 24 weeks, and the expression of the Pept1 mRNA increased 2.84-fold in intestines of obese mice subjected to long-term administration of the HFD compared with control mice at 12 weeks. Western blot showed that the trend of protein levels of Mdr1 and Mrp2 were consistent with the mRNA expression. Conclusion: The expression of uptake and efflux transporters mRNAs and protein levels were altered in obese mice compared with control mice, providing scientific evidence for future medical applications in the clinic.

Background: This study aimed to re-establish a Population Pharmacokinetic (PPK) model of oral phenytoin to further optimize the individualized medication regimen based on our previous research. Methods: Patients with intracranial malignant tumor requiring craniotomy were prospectively enrolled according to the inclusion criteria. Genotypes of CYP2C9*1 or *3 and CYP2C19*1, *2 or *3 were determined by real time PCR (TaqMan probe) method. Serum concentrations of phenytoin on the 4th and 7th day after oral administration were determined using fluorescence polarization immunoassay. The PPK parameters were estimated using Nonlinear Mixed Effects Models (NONMEM) and internal validation was performed using bootstraps. The predictive performance of the final model was evaluated by Normalized Predictive Distribution Errors (NPDEs) and diagnostic goodness- of-fit plots. Results: A total of 390 serum samples were collected from 170 patients in PPK model building group. The population typical values for Vm, Km and the apparent volume of distribution (V) in the final model were 17.5 mg/h, 6.41 mg/L and 54.8 L, respectively. Internal validation by bootstraps showed that the final model was stable and reliable. NPDEs with a normal distribution and a scatterplot with symmetrical distribution showed that the final model had good predictive capability. Individualized dose regimens of additional 40 patients in the external validation group were designed by the present final PPK model. The percentages of patients with serum concentrations within the therapeutic range were 61.53% (24/39) on the 4th day and 94.87% (37/39) on the 7th day, which were higher than the 39.33% (59/150) and 52.10% (87/167) of above 170 patients (P < 0.0001). Conclusion: The present PPK final model for oral phenytoin may be used to further optimize phenytoin individualized dose regimen to prevent early seizure in patients after brain injury if patient characteristics meet those of the population studied.

Background: Cytochrome P450 2A6 enzyme (CYP2A6), an essential hepatic enzyme involved in the metabolism of drugs, is responsible for a major metabolic pathway of nicotine. Variation in the activity of polymorphic CYP2A6 alleles has been implicated in inter-individual differences in nicotine metabolism. Aims: The objective of the current study was to assess the association between the smoking status and the cytochrome P450 2A6 enzyme (CYP2A6) genotype in Jordanians. Methods: In the current study, 218 (117 Male and 101 female) healthy unrelated Jordanian volunteers were recruited. CYP2A6*1B, CYP2A6*4 and CYP2A6*9 were determined and correlated with subject smoking status. Results: *1A/*1A was the most common genetic polymorphism in the overall study population, with no significant frequency differences between smokers and non-smokers. When the population was divided according to gender, only male smokers showed a significant correlation between genotype and smoking status. Considering the CYP2A6*9 genotype, the results showed differences in distribution between smokers and non-smokers, but only women showed a significant association between CYP2A6*9 allele genotype and smoking status. Conclusion: The results of this study show that there is a significant association between CYP2A6*9 genotype and smoking status. They also show that CYP2A6 genotype is significantly influenced by gender.